Abstract
The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26-40], median duration of response was 8.2 (95% CI, 5.6-12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval.
Highlights
Despite advancements in molecular pathogenesis and novel therapeutics in acute myeloid leukemia (AML), treatment of patients with relapsed or refractory AML (R/R AML) remains challenging without a "one-size-fits-all" approach
Given that the approval of ivosidenib was based on evaluation of a single-arm trial, it is not clear how the efficacy of ivosidenib compares to other treatment options for patients with R/R IDH1-mutated AML
Susceptible mutations are defined in the prescribing information (PI) as those leading to increased levels of 2-HG in leukemia cells and where efficacy is predicted by clinically meaningful remissions with the recommended dose of ivosidenib and/or inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods
Summary
Despite advancements in molecular pathogenesis and novel therapeutics in acute myeloid leukemia (AML), treatment of patients with relapsed or refractory AML (R/R AML) remains challenging without a "one-size-fits-all" approach. Study AG120-C-001 provided substantial evidence of efficacy and safety to support approval of ivosidenib for treatment of adults with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test. Given that the approval of ivosidenib was based on evaluation of a single-arm trial, it is not clear how the efficacy of ivosidenib compares to other treatment options for patients with R/R IDH1-mutated AML. Susceptible mutations are defined in the PI as those leading to increased levels of 2-HG in leukemia cells and where efficacy is predicted by clinically meaningful remissions with the recommended dose of ivosidenib and/or inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. Given median follow-up of only 8.3 months, there is a postmarketing requirement to provide long-term safety follow-up from the ongoing Study AG120-C-001
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